Obesity has become a major public health problem worldwide such .that in developed countries 10-20% of the adult population is obese. As the rates of obesity rise, so do associated health care costs. Few effective approaches for reducing body weight exist. Current therapeutic tools such as dietary intervention, exercise regimens, behavioral modification and even pharmacological approaches remain disappointing. The development of alternative, effective dietary regimens has significant clinical implications. Identification of efficacious dietary approaches to weight loss could provide a means by which obesity rates are curbed with significantly fewer health risks than those associated with pharmacologic or surgical interventions. Our recent work has demonstrated that hypothalamic signaling, responses to food deprivation, and sensitivity to peptides that either stimulate or inhibit food intake are dependent upon the background diet of the animal. Our overall hypothesis is that dietary macronutrients differentially influence regulatory responses to food intake. Characterization of how dietary macronutrients influence feeding-regulatory systems in terms of acute and chronic adaptive responses to maintenance on these types of diets may identify novel dietary approaches to weight management. There are three specific aims to this project. The first aim will evaluate the effects of dietary macronutrients on hypothalamic gene expression. The second aim will identify neural and endocrine systems that are affected by low carbohydrate diets. The final aim will assess how chronic exposure to ketone bodies affects feeding, body weight, and endocrine and hypothalamic controls of food intake. These experiments are necessary to further our understanding of how macronutrients influence food intake and body weight, and the mechanisms underlying differential feeding responses to chronic consumption of macronutrient-controlled diets. Furthering the basic understanding of relative contributions of dietary macronutrients to overall food intake and body weight has significant clinical implications in an environment where obesity-related disability and death continue to rise.